Unexpected toxicity events were documented during interim safety evaluations of the investigational drug.

The study is designed to assess the therapeutic efficacy of decitabine repurposing against advanced, refractory, ductal adenocarcinoma (PDAC) with molecular transcriptional signatures indicating dependency on the KRAS oncogene

TYPE OF STUDY: Phase II study, open label, multicentre, single arm, interventional, Non-randomized  TARGET POPULATION: Advanced (locally advanced or metastatic), pre-treated PDAC patients, progressing after at least one and no more than two lines of systemic therapy, whose tumors express a KRAS-dependency signature.

 RATIONALE. BACKGROUND: KRAS gene mutations occur in 95% of PDAC. Inhibitors targeting the prevalent KRASG12V and KRASG12D mutations in PDAC have yet to reach the clinical setting. Oncogenic KRAS-driven signatures have been derived from PDAC cancer models. Based on these, it is possible to identify a subset of PDACs that are highly addicted to oncogenic KRAS, and referred to as KRAS-dependent tumors (dKRAS), in which the direct targeting of KRAS or KRAS-dependent phenotypes reduced tumor growth. Notably, KRAS dependency was associated with a rewiring of nucleotide metabolism and the inhibition of pyrimidine biosynthesis was sufficient to inhibit the growth of dKRAS PDAC cells. In contrast, tumors that, though harboring KRAS mutations, do not display KRAS dependency are resistant to anti-KRAS targeting.

Decitabine (DEC) is FDA-approved for the treatment of myelodysplastic syndromes and acute myeloid leukaemia. Importantly, phase-I and -II clinical trials of DEC have defined a recommended phase II dose (RP2D) for DEC monotherapy in solid tumors.

HYPOTHESES AND RATIONALE: Preclinical studies show that DEC has cytotoxic activity and inhibits the growth of dKRAS PDAC, whereas KRAS-independent PDACs are not responsive. Based on solid preclinical studies and the scientific literature, the investigators' hypotheses are that: i) DEC is a potent anticancer drug inhibiting pyrimidine homeostasis and eliciting DNA damage in PDAC with a KRAS dependency; ii) The KRAS dependency of tumors can be analytically defined by computational scores based on the analysis of the gene expression signature on tumor biopsy; iii) These genetic scores might have a prognostic value. Based on these hypotheses, the investigators propose a proof-of-concept, biomarker-driven, phase-II clinical trial to explore the activity of DEC repurposing against advanced, refractory KRAS-dependent PDAC.

OBJECTIVES: The primary objective of the trial is to provide proof-of-concept of DEC antitumor activity in dKRAS metastatic PDAC.

Secondary objectives of the trial are to assess the feasibility of a molecularly tailored approach in advanced, pre-treated PDAC, as well as to assess treatment safety and tolerability, clinical benefit, impact on quality of life, and survival outcomes.

Inclusion Criteria:

1. Age ≥ 18 years;
2. Histologically or cytologically proven, advanced, inoperable (metastatic or locally advanced), PDAC;
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2;
4. Life expectancy of at least 12 weeks;
5. At least one and no more than two lines of systemic treatment for advanced disease;
6. At least one metastatic lesion(s) and/or primary tumor amenable to pre-treatment biopsy;
7. KRAS dependency, as assessed by molecular analysis of RNA isolated from a fresh tumor biopsy;
8. Imaging-documented progressive disease (PD), according to modified RECIST 1.1 criteria;
9. Imaging-documented measurable disease, according to modified RECIST 1.1 criteria;
10. Adequate organ and marrow function;
11. Postmenopausal status or evidence of non-childbearing status (negative urine or serum pregnancy test) for women of childbearing potential;
12. Women of childbearing potential (defined as not post- menopausal for 12 months or no previous surgical sterilization) and fertile men must agree to use two highly effective forms of contraception while they are receiving

Exclusion Criteria:

1. Uncontrolled intercurrent illness(es);
2. Pregnancy or lactation;
3. Active and uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy;
4. Major surgical intervention within 4 weeks prior to enrollment;
5. Radiotherapy, surgery, chemotherapy, or an investigational therapy within 2 weeks prior to signing the treatment ICF;
6. Any previous treatment with DEC;
7. Patients with second primary cancers, except for adequately treated non- melanoma skin cancer, curatively treated in-situ cancer of the cervix, stage 1 grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow involvement) treated with curative intent and with no evidence of active disease at >1 year from the completion of curative treatment prior to study entry;
8. Persistent toxicities (≥CTCAE grade 2) caused by previous cancer therapy, excluding alopecia;
9. Serious medical risk factors involving any of the major organ systems such that the investigator considers it unsafe for the patient to receive an experimental research drug;
10. Serious psychiatric or medical conditions that could interfere with a valid informed consent.